Uterine leiomyomata are the most common human gynecologic tumors, and recent retrospective studies report an incidence approaching 70%. Although not all of these women are symptomatic, these tumors represent a significant cause of morbidity in the United states and are responsible for over 200,000 surgeries annually. Leiomyomas are often associated with infertility and an additional 18,000 myomectomies are performed each year to reduce tumor burden while sparing the uterus. At present, non-surgical treatments include Danazol and GnRH agonists that induce a hypoestrogenic milieu, but cause important side effects including androgenization and bone loss. Following short term treatment, the tumors often return, sometimes within a few months. There is presently a controversy, that has significant therapeutic implications, concerning the relative importance of estrogen versus progesterone in the development of normal myometrium and uterine leiomyomata. One of the primary responses to estrogen in many tissues is the upregulation of PR, but the role of PR in estrogen-induced pathways of proliferation and tumorigenesis is not clear. It has been difficult to dissect out the contribution of these two hormones because of the interrelationship of the two receptor pathways including the increase in PR expression induced by estrogen. The goal of the proposed studies is to evaluate the relative contributions of progesterone and estrogen in normal and neoplastic myometrium using a recently developed PR knock-out (PR-/-) mouse. The specific aims of this project are: 1} To evaluate the role of PR in estrogen stimulated myometrial cell proliferation; 2) To determine at the molecular level which genes activated by estrogen stimulation require and functional PR, and 3} To test the hypothesis that PR plays a critical role in myometrial tumorigenesis. These studies will yield valuable mechanistic information about steroid hormone action and the relationship between hormonally induced proliferation and tumorigenesis. Results from these experiments will also provide critical insight into factors affecting leiomyomata development and could significantly impact drug development by directing efforts to specific members of relevant hormone receptor pathways.